A subset of mucosotropic human papillomaviruses (HPVs) are the principle causative agent for anogenital cancers, most notably cervical cancer. In these cancers the HPV genome is present and a subset of viral genes with oncogenic potential is expressed. These same 'high risk" (HR) HPVs now have been found in approximately 20% of human head and neck squamous cell carcinomas (HNSCC), and of these most frequently in tonsillar cancers. Notably, HPV16, the HR-HPV most commonly found in cervical cancer is the HPV most commonly found in HNSCC. Molecular analyses indicate that HPV-positive HNSCC differ from HPV-negative HNSCC, for which tobacco smoke and alcohol are the main etiological agents. Immunocompromised patients including HIV-infected individuals and organ transplant patients undergoing immunosuppressive therapy are at increased risk of HPV infections and resultant lesions in the anogenital tract and oral cavity. We have recently established the first mouse model for HPV-associated oral carcinogenesis. In this grant application, we propose studies to fully characterize this mouse model in comparison to HPV-associated human HNSCC, and to use this mouse model to assess the contributions and define the mechanisms of action of HPV16 oncogenes in oral carcinogenesis.